Tau protein in of interest to investigators from strikingly diverse vantages. Ae a microtubule-binding protein it serves as a means of probing microtubule function and dynamics. As a microtubule-associated protein that is compartmentalized within neurons, it is a window upon neuronal polarity, the establishment of axonal identity, and possibly the selective sorting of molecules or organelles to the axon. As a protein that is developmentally regulated in the expression of its isoforms, it serves as a starting point for the identification of regulators of brain development and morphology. As a phosphoprotein it leads to the characterization and function of brain kinases. And finally as a component of the Alzheimer neurofibrillary tangle, it clearly has a role in brain pathology. In the accomplishment of our specific aims during the previous grant period we have uncovered sufficient data to continue this apparently fruitful avenue of investigation. Work done during the previous grant period represents one of the first studies of the molecular bases for tau heterogeneity. In building upon the cloning and sequencing done during the original grant period we now have in hand the reagents necessary to proceed deeper into the molecular origins of tau heterogeneity, the posttranslational modifications of tau, the basis of its subcellular distribution, and finally determine which of these features might impact on the genesis of the Alzheimer neurofibrillary tangle.